The use of tyrosine kinase inhibitors (TKIs) for treating diseases related to unregulated protein kinase, signal transduction have been subject to extensive research over the past two decades. For example, the use of indolinone compounds useful for the treatment of diseases including cell proliferative diseases such as cancer, atherosclerosis, arthritis and restenonsis and metabolic diseases such as diabetes was described in U.S. Pat. No. 6,147,106.
TKIs are generally important pharmacological agents in the growing field of targeted therapy against tyrosine kinase related diseases including cancers. Indeed, a number of tyrosine kinase inhibitors are currently available for the treatment of such conditions. These include sorafenib, gefitinib, elotinib and sunitinib, all of which are currently marketed for the treatment of various cancers. There remains a need, however, for potent broad spectrum tyrosine kinase inhibitors with directed efficacy against cancer.
WO96/40116 relates to indolin-2-ones having tyrosine kinase inhibitor activity. The indolinones are substituted at the 3-position with a benzylidene group.
Ding et al, Tetrahedron Letters, 46 (2005), 5949-5951 teaches compounds similar to those of WO96/40116 as intermediates in the synthesis of spirooxindoles.
Pandit et al, Bioorg. Med. Chem., 14 (2006), 6492-6501 discloses anti-proliferative compounds which are similar to those of WO96/40116.
WO 2010/044753 and Zhang et al, Bioorg. Med. Chem. 17 (2009), 2077-2090 teach 3-benzylidene-indolin-2-one compounds which have activity as tyrosine kinase inhibitors. The present inventors have now developed further compounds which have similar activity but which have additional advantages over the compounds of WO 2010/044753.